Nociceptin (the same substance as orphanin FQ) is a peptide comprising 17 amino acid units having a similar structure to that of opioid peptide. Nociceptin has an augmenting activity on reaction against nociceptive stimulation, an appetite stimulating activity, an activity for reducing a space learning ability, an antagonism against an analgesic action of classic opiate agonists, a dopamine release inhibitory action, a water diuresis action, a vasodilative action and a systemic blood pressure-lowering action, and it is considered to take part in intracerebral controlling of pain, appetite and memory learning through the nociceptin receptor ORL1 [cf. Nature, Vol. 377, 532 (1995); Society for Neuroscience, Vol. 22, 455 (1996); NeuroReport, Vol. 8, 423 (1997); Eur. J. Neuroscience, Vol. 9, 194 (1997); Neuroscience, Vol. 75, 1 (1996); ibid., 333 (1996); Life Science, Vol. 60, PL15 (1997); ibid., PL141 (1997); Proceedings for National Academy of Sciences, Vol. 94, 14858 (1997)].
Further, it is known that morphine tolerance is reduced or memory and learning ability is improved in knockout mice in which expression of the nociceptin receptor ORL1 is inhibited [cf. Neuroscience Letters, Vol. 237, 136 (1997); Nature, Vol. 394, 577 (1998)].
It has also been reported that nociceptin itself induces symptoms resembling withdrawal symptoms observed with morphine addicts, and that a non-peptide nociceptin receptor antagonist improves morphine tolerance, dependence and symptoms resembling withdrawal symptoms [cf. Psychopharmacology, Vol. 151, 344-350 (2000); Journal of Neuroscience, Vol. 20, 7640 (2000)].
On the other hand, nociceptin protein precursor-defective mice are reported to show behaviors resembling anxiety and changes in stress response [cf. Proceedings for National Academy of Sciences, Vol. 96, 10444 (1999)].
Hence the substances which specifically inhibit binding of nociceptin to the nociceptin receptor ORL1 are useful as an analgesic against diseases accompanied with pains such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; a reliever against tolerance to a narcotic analgesic such as morphine; a reliever against dependence on or addiction to a narcotic analgesic such as morphine; an analgesic enhancer; an antiobesitic or appetite suppressor; a treating or prophylactic agent for cognitive impairment and dementia/amnesia in aging, cerebrovascular diseases and Alzheimer's disease; an agent for treating developmental cognitive abnormality such as attention deficit hyperactivity disorder and learning disability; a remedy for schizophrenia; an agent for treating neurodegenerative diseases such as Parkinsonism and chorea; an anti-depressant or treating agent for affective disorder; a treating or prophylactic agent for diabetes insipidus; a treating or prophylactic agent for polyuria; a remedy for hypotension, and the like.
Substances which specifically inhibit binding of nociceptin to the nociceptin receptor ORL1 are disclosed, for example, in WO99/029696, WO00/27815, WO01/83454, WO03/40099, WO03/64425. These compounds all have a skeleton having a cycloalkane condensed with a benzene nucleus, which, however, differ from the compounds of the present invention in point of the skeleton thereof. Precisely, the compounds of the present invention has a skeleton having a cycloalkane condensed with a pyridine nucleus.
On the other hand, Tetrahedron Letters, Vol. 41, pp. 9829-9833 (2000) discloses a compound having the following structure:

The compound was developed as a derivative of haloperidol, and its effect and mechanism differ from those of the compounds of the present invention.
Patent Reference 1: WO99/029696
Patent Reference 2: WO00/27815
Patent Reference 3: WO01/83454
Patent Reference 4: WO03/40099
Patent Reference 5: WO03/64425
Non-Patent Reference 1: Tetrahedron Letters, Vol. 41, pp. 9829-9833 (2000)